CYP2D6 Genetic Polymorphisms and Risperidone Pharmacokinetics: A Systematic Review and Meta-analysis

Area of Science:

• Pharmacogenomics
• Drug Metabolism
• Clinical Pharmacology

Background:

• Risperidone, a second-generation antipsychotic, is metabolized by cytochrome P450 (CYP) 2D6 and CYP3A4.
• The influence of genetic variations in drug metabolism on risperidone and its active metabolite (9-hydroxyrisperidone) exposure remains unclear.

Purpose of the Study:

• To systematically review and meta-analyze the impact of genetically defined CYP2D6 enzyme activity on risperidone pharmacokinetics.
• To evaluate how CYP2D6 genotype influences the exposure of risperidone and its active moiety.

Main Methods:

• A comprehensive literature search identified studies investigating the relationship between CYP2D6 genetic variations and risperidone pharmacokinetics.
• Subjects were categorized into CYP2D6 poor, intermediate, normal, and ultrarapid metabolizer groups using a standardized genotype-phenotype translation system.
• Dose-adjusted serum/plasma concentrations and area under the concentration-time curve were used to measure drug exposure.

Main Results:

• The meta-analysis included 15 studies with 2125 adult subjects.
• Compared to normal metabolizers, intermediate metabolizers had 2.35-fold higher risperidone concentrations, and poor metabolizers had 6.20-fold higher concentrations after multiple oral doses.
• Active moiety concentrations were 1.18-fold higher in intermediate and 1.44-fold higher in poor metabolizers, with similar trends observed in single-dose studies.

Conclusions:

• Genetically determined reduced CYP2D6 activity is linked to increased exposure to risperidone and its active metabolite in adults using oral formulations.
• Further research is required to determine the clinical significance of these genetic associations.